AUTHOR=Tiburcio Rafael , Melo Léon Dimitri , Nunes Sara , Barbosa Ana Luísa Augusto , de Oliveira Elaine Carvalho , Suarez Martha , Borges Valéria M. , Tavares Natalia , Brodskyn Claudia Ida 

TITLE=DC-SIGN Mediates the Interaction Between Neutrophils and Leishmania amazonensis-Infected Dendritic Cells to Promote DC Maturation and Parasite Elimination

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.750648

DOI=10.3389/fimmu.2021.750648

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Leishmaniasis is a neglected arthropod-borne disease that affects millions of people worldwide. Successful <italic>Leishmania</italic> infections require the mitigation of immune cell functions leading to parasite survival and proliferation. A large body of evidence highlights the involvement of neutrophils (PMNs) and dendritic cells (DCs) in the establishment of immunological responses against these parasites. However, few studies, contemplate to what extent these cells interact synergistically to constrain <italic>Leishmania</italic> infection.</p></sec><sec><title>Objective</title><p>We sought to investigate how PMNs and infected DCs interact in an <italic>in vitro</italic> model of <italic>Leishmania amazonensis</italic> infection.</p></sec><sec><title>Material and Methods</title><p>Briefly, human PMNs and DCs were purified from the peripheral blood of healthy donors. Next, PMNs were activated with fibronectin and subsequently co-cultured with <italic>L. amazonensis</italic>-infected DCs.</p></sec><sec><title>Results</title><p>We observed that <italic>L. amazonensis</italic>-infected DC exhibited lower rates of infection when co-cultivated with either resting or activated PMNs. Surprisingly, we found that the release of neutrophil enzymes was not involved in <italic>Leishmania</italic> killing. Next, we showed that the interaction between PMNs and infected-DCs was intermediated by DC-SIGN, further suggesting that parasite elimination occurs in a contact-dependent manner. Furthermore, we also observed that TNFα and ROS production was dependent on DC-SIGN-mediated contact, as well as parasite elimination is dependent on TNFα production in the co-culture. Finally, we observed that direct contact between PMNs and DCs are required to restore the expression of DC maturation molecules during <italic>L. amazonensis</italic> infection.</p></sec><sec><title>Conclusion</title><p>Our findings suggest that the engagement of direct contact between PMNs and <italic>L. amazonensis</italic>-infected DC <italic>via</italic> DC-SIGN is required for the production of inflammatory mediators with subsequent parasite elimination and DC maturation.</p></sec>